Development and evaluation of a multi-cancer screening (MCS) test for cancers common in Asia.
Authors: Michelle Pek, Hao Chen, Zi Yi Wan, Kao Chin Ngeow, Boon C. Goh, Siu Kie Au, Wai Meng David Tai, Joycelyn Jie Xin Lee, Zi Yi Lim, Iain B. Tan, Dawn Q Chong, Chwee Ming Lim, Ravindran Kanesvaran, SuPin Choo, Min-Han Tan
Journal: Journal of Clinical Oncology (2023)

3052 Background: The majority (78%) of cancer deaths in Asia arise from cancers with no existing screening recommendations. Earlier cancer detection is associated with improved outcomes. While single-cancer screening by liquid biopsy (notably plasma EBV DNA for nasopharyngeal cancer) is recognized in Asia, multi-cancer screening (MCS) liquid biopsy testing is a potential opportunity to address this key need. We developed a ctDNA mutation-based testing workflow based on targeted amplicon-based next generation sequencing testing of plasma and matched buffy coat as required to exclude clonal hematopoiesis, with a custom pipeline incorporating clinico-demographic factors for tissue-of-origin (TOO) calling. Methods: Primary objectives were to evaluate assay performance for detection of cancer-associated alterations, as well as TOO prediction accuracy. Validation was performed on a sample cohort of 476 untreated patients, each with 1 of 10 different cancers (lung, liver, breast, colorectal, prostate, nasopharyngeal, pancreas, bile duct, acute and chronic myeloid leukemia). 50 initial age-matched healthy controls were also used. A weighted sum model was used for TOO prediction, which was evaluated in an expanded 1478-sample cohort. Weights assigned to each cancer-associated alteration and its co-occurring combinations represent the importance or contribution of each alteration to each potential TOO. The impact of inclusion of clinico-demographic data (where available) on TOO prediction was also evaluated. Results: Overall sensitivity for detection of cancer-associated alterations was 72.7% (346/476). Sensitivity is higher in metastatic cases (82.5%) compared to localized cases (41.8%). Sample-level specificity for cancer-associated alterations/EBV detection was 96% (48/50), also comparable to previous series. Cancer-associated alterations/EBV were detected in approximately 50% of localized cases for 3 cancer types with no established screening recommendations in Asia (lung - 54.6%; bile duct - 50.0%; pancreas - 48.6%). In the expanded cohort, a high confidence call for TOO was obtained in 55.4% (818/1478) of samples with positive findings. Clinico-demographic data inclusion as a model variable improved overall TOO prediction accuracy in 10 cancer types to 93.8% (767/818), compared to an accuracy of 90.2% without factoring in clinico-demographic data. Conclusions: The MCS ctDNA assay shows reasonable sensitivity and specificity for detection of cancer-associated alterations, based on a retrospective study cohort. Tumor TOO can also be correctly classified in the majority of patients. Incorporation of clinico-demographic data to personalize TOO recommendations also improved accuracy of calls. Further prospective studies and the addition of multi-omic capabilities will continue to be helpful to determine MCS performance in an Asian multi-ethnic environment.